Toxoplasma gondii is an obligate intracellular parasite capable of infecting most warm-blooded vertebrates and many nucleated cell types. Parasite transmission occurs orally through ingestion of tissue cysts or sporozoites from feline feces in contaminated soil, food, and water. Infection typically results in an asymptomatic primary infection that leads to a chronic latent infection affecting 30% of the world's population (Carruthers (2002) Acta Trop. 81:111-122). Following oral ingestion of tissue or oocyst cysts, parasites are released into the gut mucosa where they infect host cells and transform into the rapidly replicating tachyzoite stage. Rapidly replicating tachyzoites disseminate widely throughout the host reaching most organs and the brain. Host immune pressure is thought to trigger differentiation of tachyzoites into slow growing bradyzoites and development of tissue cysts. Despite the potent Th-1 acquired immunity that is elicited by primary infection, tissue cysts persist in immune privileged sites such as the brain for the life of the host. The reactivation of bradyzoites to tachyzoite differentiation in brain cysts leads to recrudescent and life threatening Toxoplasmic encephalitis in AIDS patients (Luft and Remington (1992) Clin. Infect. Dis. 15:211-222). T. gondii primary infections in pregnancy also lead to spontaneous abortion or severe CNS damage in neonates. As T. gondii is the 3rd leading cause of food-born illness in the U.S., it is a significant human pathogen and therefore understanding the mechanisms underlying the development of protective immunity in response to infection is of high importance to development of vaccines.
T. gondii is now a widely recognized model for host response mechanisms. During active infection, T. gondii induces a potent systemic Th-1 inflammatory response that results in life long CD8+ T cell-mediated immune control of the infection. Infection triggers the innate response through a MyD88-dependent pathway resulting in IL-12-independent production of IFN-γ by NK and T cells leading to the recruitment of neutrophils and macrophages to the site of infection (Scanga, et al. (2002) J. Immunol. 168:5997-6001; Mun, et al. (2003) Int. Immunol. 15:1081-1087; Scharton-Kersten, et al. (1996) Exp. Parasitol. 84:102-114). Concomitant with the innate response, the development of the acquired Th-1 response is driven by secretion of IL-12 from neutrophils, macrophages and DCs that increases inflammatory cell infiltration, activates APCs and enhances production of IFN-γ by T cells and NK cells leading to the cell-mediated immune control (Bennouna, et al. (2003) J. Immunol. 171:6052-6058; Gazzinelli, et al. (1994) J. Immunol. 153:2533-2543).
Certain mechanisms of the immune response and key mediators of host immune control have been defined. Previous studies of host responses have typically used replicating and infectious strains of T. gondii that widely disseminate and cause extensive host tissue destruction and associated host-derived inflammatory responses. Other immune response models are based on studies using whole parasite antigen or parasite components (Scanga, et al. (2002) supra; Mun, et al. (2003) supra; Scharton-Kersten, et al. (1996) supra; Bennouna, et al. (2003) supra; Gazzinelli, et al. (1994) supra; Aliberti, et al. (2000) Nat. Immunol. 1:83-87). These host response and vaccine models reveal that immunization with weakened, but living and invasive T. gondii parasites results in complete protection against lethal challenge infections (Waldeland and Frenkel (1983) J. Parasitol. 69:60-65; Snzuki and Remington (1988) J. Immunol. 140:3943-3946; Bourguin, et al. (1998) Infect. Immun. 66:4867-4874; Kasper, et al. (1985) J. Immunol. 134:3426-3431).